Abstract

Objective

Methods

The results of studies of a suitable size in colonic adenoma and arthritis—that had been published in English and from which crude data about MIs could be extracted—were evaluated. Medline, Embase and Cinahl (2000–2006) databases, as well as published bibliographies, were used as data sources. Systematic reviews examined MI risks in case‐control and cohort studies, as well as in randomised controlled trials (RCTs).

Conclusion

The overall risk of MI with NSAIDs and cyclo‐oxygenase‐2‐specific drugs was small; rofecoxib showed the highest risk. There was an increased MI risk with cyclo‐oxygenase‐2‐specific drugs compared with NSAIDs, but less serious upper gastrointestinal toxicity.

Emphasis on the adverse effects of non‐steroidal anti‐inflammatory drugs (NSAIDs) has moved from their upper gastrointestinal (GI) to their cardiovascular toxicity.1 This reflects widespread concern that cyclo‐oxygenase‐2‐specific drugs in general, and rofecoxib in particular, increase the risk of myocardial infarction (MI) compared with traditional NSAIDs.2 Like other cyclo‐oxygenase‐2‐specific drugs, rofecoxib minimises serious GI toxicity whilst retaining anti‐inflammatory efficacy. Although these benefits have been established experimentally in randomised controlled trials (RCTs), a large trial by Bombardier et al3 (the Vigor trial) showed an excess of MIs with rofecoxib. When a second RCT in colonic adenoma also reported an excess of MIs, rofecoxib was withdrawn worldwide.4 Since then, there has been substantial debate about the risk of MI with cyclo‐oxygenase‐2‐specific drugs in particular and with NSAIDs in general.

In addition to the debate amongst clinicians and patients on the cardiovascular toxicity of NSAIDs, regulators have also taken different views. The US Food and Drug Administration (FDA)5 has concluded that there are significant cardiovascular risks with all NSAIDs, while the European Medicines Agency has concluded that cyclo‐oxygenase‐2‐specific drugs present only specific risks.6,7 Any potential risk of MI needs to be placed in the context of the overall risks of serious events with NSAIDs, including upper GI events. The authors have therefore evaluated the available published evidence by undertaking systematic reviews of the risk of MI with cyclo‐oxygenase‐2‐specific drugs and traditional NSAIDs in observational studies, and with cyclo‐oxygenase‐2‐specific drugs in RCTs in a non‐rheumatic disease (colonic adenoma) and in arthritis. Other published systematic reviews of MI in RCTs of cyclo‐oxygenase‐2‐specific drugs were also examined, to ensure consistency in interpretation. Finally, the risks of MI and serious upper GI events in RCTs of cyclo‐oxygenase‐2‐specific drugs in arthritis were compared.

Methods

Search strategies

Medline, Embase and Cinahl databases (January 2000 to June 2006) were searched to find both primary references and published systematic reviews. The authors also searched published bibliographies and the Cochrane Library. The following search terms were used: non‐steroidal anti‐inflammatory drugs, Cox‐2 inhibitors, rofecoxib, celecoxib, lumiracoxib, valdecoxib, etoricoxib, ibuprofen, diclofenac, naproxen, myocardial infarction, ischaemic heart disease, colonic adenoma and colonic neoplasm. Both generic and proprietary drug names were used as search terms. The authors only considered studies published in English. Studies that contained insufficient information about cardiac adverse events to enable the assessment of the presence or absence of MIs, or from which raw numerical data about MIs could not be extracted, were excluded. Studies of meloxicam were also excluded due to the debate on its degree of cyclo‐oxygenase‐2 selectivity.8,9

Types of study

Four relevant categories of peer‐reviewed paper were identified:

case‐control and cohort studies that examined the association between the occurrence of MI and NSAIDs, and that had enrolled at least 100 patients;

RCTs of NSAIDs in patients with colonic adenoma, where at least 100 patients had been enrolled;

RCTs comparing cyclo‐oxygenase‐2‐specific drugs with traditional NSAIDs in arthritis, where at least 100 patients had been enrolled; these studies were also evaluated to assess the development of complicated upper GI ulcers, defined by Silverstein et al10 as perforation, obstruction or upper GI bleeding;

published systematic reviews of RCTs of cyclo‐oxygenase‐2‐specific drugs focusing on the occurrence of MIs.

Details of the case‐control studies, cohort studies and RCTs evaluated are summarised in table 1​1.

Table 1Details of the studies included in the systematic reviews

Data extraction

Two researchers independently assessed studies for eligibility and extracted data on year of publication, population source, study design, study size, study setting, case definition, exposure definition, reference group, funding source, study period and outcomes. Where their initial conclusions did not agree (in the case of two studies), the researchers reviewed these studies together and reached a joint conclusion.

Statistics

The results from observational studies and RCTs were analysed using Review Manager V.4.2 (Nordic Cochrane Centre, Denmark). The relative risk (RR) of MI in RCTs and cohort studies, and the random‐ and fixed‐effects odds ratios (ORs) in case‐control studies were evaluated. In studies with few or no events the Peto OR was used.

To assess for heterogeneity in the observational studies, separate subgroup meta‐analyses were carried out. Stratification was by sample size, country of study, source of funding, study design (matched versus unmatched) and definition of exposure for the case‐control studies, and by type of study design for the cohort studies. In addition, a funnel plot was produced to look for publication bias in the case‐control studies.

Quality

The quality of the RCTs was judged using the Jadad scoring instrument.11 Non‐RCT studies were judged using factors recommended by the Standards for the Reporting of Observational Studies in Epidemiology Group12; the authors scored six items (items 6–11) from the second version of the STROBE statement (STrengthening the Reporting of OBservational studies in Epidemiology) checklist.13

Results

Systematic review of MI in observational studies of NSAID use

Out of a total of 806 studies found, 705 were retrieved that were in English and involved human subjects, and 24 potentially relevant studies were identified. Four of these were excluded because they evaluated only one or two drugs or did not have suitable comparable groups.14,15,16,17 Fourteen studies had case‐control designs (including one retrospective cohort study analysed using a case‐control approach) and six had cohort designs (​(tablestables 2 and 3​3).18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37

The 14 case‐control studies enrolled 74673 MI patients who were either taking NSAIDs or had recent exposure to NSAIDs and 368968 comparable controls.18,19,20,21,22,23,24,25,26,27,28,29,30,31 Twelve of these studies evaluated NSAID use from prescription data and two used telephone interviews. Overall, there was no significant association between NSAID use and MI (fig 1​1)) using a random‐effects model (OR 1.17; 95% CI 0.99 to 1.37), but there was a small risk of MI using a fixed‐effects model (OR 1.32; 95% CI 1.29 to 1.35). Sensitivity analysis (​(tablestables 2 and 3​3)) showed that a number of factors influenced potential risk. ORs (fixed and random) were larger in studies that involved substantial numbers of patients, only enrolled European patients, had matched controls and did not involve industrial sponsorship. Evaluating the risks of individual commonly used drugs showed that the highest risks were with rofecoxib (OR 1.19 and 1.14, respectively, in random‐effects and fixed‐effects models). Other NSAIDs—celecoxib, diclofenac, ibuprofen and naproxen—showed either no increased or minimally increased risks in these models (​(tablestables 2 and 3​3).). Two studies evaluated the effects of different rofecoxib doses using the random‐effects model; high doses (>25 mg daily) showed a greater risk of MI (OR 2.9; 95% CI 1.2 to 7.0) than lower doses (OR 1.3; 95% CI 1.1 to 1.5).25,29

The six cohort studies enrolled 529090 patients (387983 years of follow‐up) currently taking NSAIDs and 604871 controls (1120812 years of follow‐up).32,33,34,35,36,37 They identified NSAID use from prescription data. There was no overall risk (fig 1​1)) of developing MI whilst receiving NSAIDs (RR 1.03; 95% CI 1.00 to 1.07). Rofecoxib, but none of the other commonly used NSAIDs (​(​tablestables 2 and 3​3),), showed an increased risk of MI (RR 1.25; 95% CI 1.17 to 1.34). One study evaluated the effects of different rofecoxib doses33; the relative risk of MI with high doses (>25 mg daily) was 1.6 (95%CI 0.9 to 2.8) and with lower doses was 1.1 (95% CI 0.8 to 1.4), but neither difference was significant.

Both meta‐analyses showed significant heterogeneity (case‐control studies, χ2 622, df 13, p<0.001; cohort studies, χ2 63, df 5, p<0.001). In the case‐control studies, subgroup analysis suggested that country of study, sample size and definition of NSAID exposure (prescription data versus telephone interview) all contributed to the heterogeneity, while funding source did not. A funnel plot showed some evidence of publication bias, and there is evidence for an over‐reporting of small negative studies (fig 2​2).). In the cohort studies, removing one study whose design was significantly different (case‐control study analysed as a cohort study) reduced the heterogeneity considerably (χ2 27, df 4, p<0.001).35 However, with both types of study, despite subgroup stratification, there was there was still significant unexplained residual heterogeneity.

Systematic review of MI in RCTs of NSAIDs in colonic adenoma

Out of a total of 220 studies found in colonic adenoma, 167 that were published in English and involved human subjects were retrieved, and 26 were identified as potentially relevant. Only four of these were large placebo‐controlled RCTs of NSAIDs in colonic adenoma4,38,39,40; we specifically omitted the low‐dose aspirin group (82 mg) used in one of these trials from our review, as this dose is never used for its anti‐inflammatory effects.38 The RCTs in these studies involved aspirin, rofecoxib and celecoxib, with half the celecoxib‐treated patients taking a dose higher than that recommended in routine practice (800 mg daily). These studies enrolled 3332 cases and 2668 controls; 44 cases and 13 controls experienced an MI. As fig 3​3 shows, the risk of MI was increased for all three NSAIDs studied (RR 2.68; 95% CI 1.43 to 5.01).

Systematic review of MI in RCTs of NSAIDs in arthritis

Seven relevant published systematic reviews in arthritis reporting cardiovascular adverse reactions with celecoxib (three reviews), rofecoxib (two reviews), lumiracoxib (one review), and all cyclo‐oxygenase‐2‐specific drugs and traditional NSAIDs (one review) were identified.1,41,42,43,44,45,46 We excluded four systematic reviews that did not focus on MIs.47,48,49,50

The four most recently published systematic reviews1,43,44,45 that focused on MI summarised 138 trials involving 145373 patients (table 4​4).). All reported small increases in the risk of MI with cyclo‐oxygenase‐2‐specific drugs. The highest risk was with rofecoxib (RR 2.2; 95% CI 1.2 to 4.0) and this risk was most marked at high doses (RR 2.8; 95% CI 1.2 to 6.4). An additional systematic review specifically compared celecoxib with placebo and other comparators in six RCTs enrolling 12780 patients; it found an increased risk of MI with celecoxib (OR 1.88; 95% CI 1.15 to 3.08). These systematic reviews did not specifically compare the risk of MI with the risk of serious upper GI events.

Comparison of MI with serious upper GI events in RCTs of cyclo‐oxygenase‐2‐specific drugs

Out of a total of 452 studies found, 188 were retrieved that were in English and involved human subjects; of these, 50 RCTs were identified that reported comparisons of cyclo‐oxygenase‐2‐specific drugs with traditional NSAIDs. Thirty‐six RCTs were excluded as they gave insufficient information about the occurrence of MIs.51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86 The remaining 14 RCTs allowed comparisons of MI with serious upper GI adverse events.3,10,87,88,89,90,91,92,93,94,95,96,97,98 These trials enrolled 45425 patients into active treatment groups receiving either a cyclo‐oxygenase‐2‐specific drug or a traditional NSAID; they reported 97 MIs. Three trials used double the highest‐recommended long‐term doses of cyclo‐oxygenase‐2‐specific drugs.3,10,90 We also took into account recently published additional data about the number of MIs in the Vigor trial.99 There was a significant increase in the number of MIs with cyclo‐oxygenase‐2‐specific drugs (Peto OR 1.6; 95% CI 1.1 to 2.4), as shown in table 5​5.. This increase was mainly due to the results from a single trial, the Vigor trial that compared rofecoxib with naproxen.3

Table 5Comparison of the risks of myocardial infarction (MI) and complicated ulcers in RCTs of cyclo‐oxygenase‐2‐specific drugs

These trials also resulted in 216 serious upper GI events and cyclo‐oxygenase‐2‐specific drugs decreased the risk of serious upper GI events (Peto OR 0.40; 95% CI 0.31 to 0.53). Complicated upper GI events occurred in 61 patients given cyclo‐oxygenase‐2‐specific drugs and 155 patients given traditional NSAIDs. In contrast, MIs occurred in 61 patients given cyclo‐oxygenase‐2‐specific drugs and 36 patients given traditional NSAIDs. Consequently, reductions in complicated upper GI events with cyclo‐oxygenase‐2‐specific drugs occurred at the same time as an increase in MIs.

Discussion

The overall risk of MI does not appear to be substantially increased with standard doses of most traditional NSAIDs and most cyclo‐oxygenase‐2‐specific drugs. Rofecoxib consistently showed a significant increase in the risk of MI in all types of study. Some other cyclo‐oxygenase‐2‐specific drugs and some traditional NSAIDs showed small increases in the risk of an MI in certain types of study, particularly in case‐control studies analysed using a fixed‐effects OR model. This analysis includes all types of peer‐reviewed evidence, ranging from observational studies of NSAID use in MI patients to RCTs in colonic adenoma and an overview of NSAID RCTs in arthritis. It compares MI and GI risks in RCTs of NSAIDs. It is also independent of pharmaceutical companies and government agencies.

The most definitive evidence that NSAIDs increase the risk of MI comes from RCTs in patients with colonic adenoma who, in comparison with patients with rheumatoid arthritis, do not have a specific pre‐existing cardiovascular risk. However, as the number of these trials is small, caution is required in generalising their findings. One RCT involved a supratherapeutic dose of celecoxib (800 mg daily) and may not be relevant to patients using standard doses. The apparent risk with aspirin is based on limited evidence; one RCT on aspirin that was evaluated showed a high RR of 5.0 (95% CI 0.6 to 43.5) for MI, but the study's small size means that this risk is not significant.38 However, in support of the view that anti‐inflammatory doses of aspirin may increase serious vascular side‐effects, the combined frequency of MI and stroke with 323 mg aspirin was significantly increased in this trial (10 events with aspirin, one event with placebo; RR 10.0 (95% CI 1.3 to 77.7)). These findings must be set against the negative effects of low‐dose aspirin in the same study (omitted from the formal systematic review), which suggests that dosing may be of critical importance.

Although RCTs in arthritis comparing cyclo‐oxygenase‐2‐specific drugs with traditional NSAIDs show an excess of MIs, this finding is heavily influenced by a single RCT of rofecoxib: the Vigor trial.3 Not only did this trial exclusively enrol patients with rheumatoid arthritis, who have an underlying increased frequency of MI, but it also compared double the recommended dose of rofecoxib with traditional doses of naproxen.100 Its relevance to routine practice is therefore uncertain. The data about MI risks from traditional NSAIDs are weak. RCTs performed before 2000 did not routinely report MIs and almost all these studies were of a relatively small size and short duration. Even a 5‐year RCT of traditional NSAIDs that enrolled 802 patients with osteoarthritis did not specifically report MIs, although there were more cardiovascular adverse events with indomethacin (12/202 (6%) cases) than with placebo (8/303 (3%) cases).101 The dearth of data on MI before 2000 makes it impractical to assess cardiac risks in these earlier RCTs.

We found that some case‐control studies showed a small overall increase in the risk of MI, particularly with rofecoxib; however, cohort studies indicated no overall added risk. A number of factors—including small study size, selection of potentially inappropriate controls and the population studied—influenced the assessment of risk. A number of confounding factors may also affect the results in these observational studies. Patients given different NSAIDs may have different underlying MI risks; for example, cyclo‐oxygenase‐2‐specific drugs were recommended for patients over 65 years of age, who often have underlying MI risks, and case‐control studies could therefore overestimate their MI risks. We did not correct for variations in risk factors because individual studies require different types of correction; however, the counter‐arguments in favour of such correction are acknowledged.102

Another confounding factor, confounding by indication, seems more important and cannot be overcome by corrections. It is exemplified by a Danish mortality study with paracetamol, which reported a standardised mortality rate for MI of 1.6 in 50000 patients prescribed paracetamol.103 The most likely explanation for this relationship is that patients who are unwell with conditions such as ischaemic heart disease often take a readily available symptomatic remedy such as paracetamol. This is an example of confounding by indication, and such confounding may explain some or all of the association of NSAIDs with MIs in observational studies.

Furthermore, many reviews use not only published data but also material provided by pharmaceutical companies or obtained from regulatory bodies, such as the FDA, for the sake of completeness. However, we only evaluated data published in peer‐reviewed journals because we believe that such papers meet a guaranteed standard of reporting that is less prone to idiosyncratic variability and maintains independence.

Given the importance of cardiovascular safety with NSAIDs, it is unsurprising that several groups have reported systematic analyses of RCTs1,41,42,43,44,45 and observational studies.104 These studies have evaluated different data based on varying search and selection strategies. However, their main conclusions mirror our own: a definite risk with rofecoxib, a possible risk with diclofenac, and small or nonexistent risks with other cyclo‐oxygenase‐2‐specific drugs and traditional NSAIDs. The interpretation of the findings varies between reviews, reflecting the different values of individual authors when faced with complex data. Interestingly, although it was published after the search period of our review, the Medal trial—which compared etoricoxib with diclofenac in over 34000 patients—found no difference in the risk of MI between these two drugs.105 The interpretation of this result depends on the assessment of risk with diclofenac, which the results of our review suggest is above that with some other traditional NSAIDs.

Cyclo‐oxygenase‐2‐specific drugs were developed to meet the need for effective NSAIDs with improved GI safety. In retrospect, this aim was incomplete; the key need is improved overall safety. Falling GI risks with NSAIDs, reflecting the use of reduced doses of traditional NSAIDs and the co‐prescribing of proton‐pump inhibitors, emphasise the need to evaluate overall safety.106 Rofecoxib reduced serious GI toxicity but increased the risk of MI, giving it a different side‐effect profile to traditional NSAIDs. The increased risks of MIs with rofecoxib together with its improved GI safety ensured that overall it was neither more nor less safe than conventional NSAIDs. Part of the concern about rofecoxib107,108 reflects the representation of its relative safety.109,110 In this context, although reports of cardiac risks with cyclo‐oxygenase‐2‐specific drugs imply that naproxen is a safe NSAID, a study of 18424 deaths in individuals who were prescribed NSAIDs found that mortality was highest with naproxen (2.7 times the mortality with nabumetone) and that it was the least safe of four traditional NSAIDs.111

Taken as a whole, the available evidence suggests that the risks of MI with NSAIDs other than rofecoxib are not large, especially when compared with preventable MI risk factors such as smoking.112 The risks of most side‐effects of NSAIDs are greatest when high doses are given for prolonged periods to elderly patients and such an approach should be avoided. The multiplicity of cardiovascular side‐effects with NSAIDs—particularly hypertension and fluid retention—mean that caution should also be exercised when considering the prescription of NSAIDs for patients with high cardiovascular risk. However, for some patients with severe arthritis there may be no realistic alternative and they will need access to effective treatment with information about its risks and benefits. Giving patients informed choice about risks and being involved in taking decisions about therapy is supported by recent regulatory guidance.113 Finally, economic and decision analyses do not favour cyclo‐oxygenase‐2‐specific drugs in the majority of cases, although they recognise that some patients benefit from these drugs.114,115

Acknowledgements

The research forms part of an overarching project in the Department of Rheumatology at King's College on assessing the risks and benefits of the different treatments for arthritis to deliver quality clinical care. We are pleased to acknowledge financial support for this study from the Arthritis Research Campaign (Programme Grant S0682 and Integrated Clinical Arthritis Centre Grant P0572) and from National Health Service R&D Support Funding to University Hospital Lewisham and Kings College Hospital.

Abbreviations

GI - gastrointestinal

MI - myocardial infarction

NSAID - non‐steroidal anti‐inflammatory drug

OR - odds ratio

RCT - randomised controlled trial

RR - relative risk

Footnotes

Competing interests: PAS, GHK and CMS have received no direct payments from companies involved in the evaluation or marketing of non‐steroidal anti‐inflammatory drugs in the last 5 years, including support to attend meetings, fees for consulting, and funding for research or educational support. EHC and DLS have received clinical trial grants, unrestricted educational grants and personal sponsorship for attending meetings from many companies involved in clinical trials and marketing of current anti‐rheumatic drugs, including all those involved in cyclo‐oxygenase‐2‐specific drugs. DLS has received fees for speaking at meetings, membership of national and international advisory boards, and giving professional advice from many pharmaceutical companies in the last 5 years including Amgen, Merck Sharp and Dhome, Novartis, Pfizer, Sumitomo Pharmaceuticals and Wyeth. He is medical adviser to Arthritis Care and Medical Vice‐Chair of the Arthritis and Musculoskeletal Alliance, which have both received unrestricted grants from pharmaceutical companies. No pharmaceutical company or adviser or representative has been involved directly or indirectly in the inception, preparation or writing of this manuscript; its contents have not been disclosed to any pharmaceutical company before submission.